Acute lung injury (ALI) is a major clinical problem in the United States with an estimated incidence rate of 262,500 patients (1) and 40-50% mortality (2, 3). ALI is characterized by severe alveolar damage resulting from an acute inflammatory response that leads to neutrophil infiltration, edema, and formation of fibrotic lung tissue (4). The fundamental mechanism of this serious condition evolves from an imbalance between excess pro- versus anti- inflammatory cytokines (5). Correcting this imbalance may offer a logical solution to ALI prevention. Cytokine signaling is mediated via the Janus family tyrosine kinases (JAKs), which activate cytokine receptors, creating docking sites for SH2-containing proteins, such as the signal transducer and activator of transcription-1 (STAT1), an important contributor to the production of inflammatory cytokines/chemokines. The suppressor of cytokine signaling 1 (SOCS1) protein is a physiologic regulator of cytokine production and has been shown to be the most efficient inhibitor of STAT1 activation (6, 7). Significantly, animals deficient in SOCS1 die from complications associated with severe inflammation, characterized by hematopoietic infiltration of numerous organs, including the lungs, which is strikingly similar to the clinical manifestation of ALI. This suggests that SOCS1 is a key regulator of inflammation in the lung. However, the physiologic levels of SOCS1 are not sufficient to stem the deleterious effects of uncontrolled inflammation. We hypothesize that therapeutic supplementation of intracellular stores of these inhibitory molecules will prevent or lessen the deleterious effects of excessive inflammation in the lung. To test this hypothesis we will construct a cell-penetrating (CP) form of SOCS1 (CP-SOCS1) and analyze its ability to traverse the cell membranes of established and primary cell lines. In addition, we will analyze CP-SOCS1- treated cells for inhibition of STAT1 activation and cytokine production in response to interferon-gamma or pathogen-derived inducers Staphlococcal enterotoxin B (SEE) and lipopolysacharide (LPS). Subsequently, we will focus on the ability of CP-SOCS1 to prevent cytokine production, lung injury, and lethality after parenteral delivery to mice in an acute lung injury model induced by SEB and LPS. We will also compare the effectiveness of CP-SOCS1 with currently available CP-SOCS3. The proposed studies are expected to advance our understanding of the fundamental mechanism of ALI and offer an innovative bench to bedside approach to this vexing clinical problem. Respiratory tract infections caused by bacteria can result in excessive inflammation and injury to lung. We propose to develop a therapeutic agent that will minimize lung damage while preserving the ability of the immune response to clear infection.